We propose to create and study a new family of biomimetic oligomers for antibacterial applications. In particular, we aim to create biostable, functional mimics of natural antimicrobial peptides (AMPs), which are an integral and effective part of the host-defense systems of myriad organisms ranging from humans to bacteria. By preferentially binding to and disrupting or permeating bacterial cell membranes, these surface- active peptides are able to kill a broad spectrum of microorganisms. Many are also selective, causing no harm to mammalian cells. The killing mechanism, while imperfectly understood, is sufficiently general that bacteria have been unable to evolve resistance to AMPs over millions of years. Thus, good functional mimics of AMPs hold forth the promise of serving as a new class of antibiotic compounds, which could act in solution directly or be tethered to the surfaces of biomedical devices to stave off infection. We propose to create non-natural mimics of AMPs, since peptides themselves are vulnerable to proteolysis and hence degrade too rapidly in the body, and moreover because peptides are often immunogenic in vivo. In particular, our novel mimics will be based on amphipathic, sequence-specific oligo-N-substituted glycines ("peptoids"). Peptoids are quite similar in structure to peptides, yet are protease-resistant. They are easily synthesized by a high-yielding, solid-phase protocol that allows the easy incorporation of biomimetic side chains. Moreover, peptoids can be designed to form stable, biomimetic helices that keep their folded structure in both aqueous and biomembrane environments, and which are highly resistant to denaturation. In preliminary work, we have shown that certain peptoid sequences (9-17mers) designed to mimic the amphipathic sequence patterning and helical structure of antimicrobial peptides are potent and selective antibacterials (MIC ~ 4 [unreadable]M against E. coli and 820 nM against B. subtilis, with negligible hemolysis at the E. coli MIC). We propose to further study and develop these compounds, by (1) exploring structure-function relationships and mechanism(s) of action through detailed biophysical studies of a "basis set" of closely related peptoids with differing potency/selectivity profiles, (2) creating novel peptoids that mimic structural motifs of natural AMPs, including peptoids that are lipidated, cyclized, and kinked;(3) testing their antibiotic activity against antibiotic-resistant bacteria as well as early-stage investigation of their toxicity to human cells.